From ACE2 depletion, hyperactivation of platelets and endothelial dysfunction to thrombosis: introducing CAC
Other than most "commonly recurring" viruses, SARS-coronaviruses (the viruses that lead to COVID, severe respiratory illness) have a prospensity to cause thrombosis. In the case of COVID, microclots indiscriminately appear in all age groups, irrespective of underlying medical conditions. Since 2003, it has become increasingly clear why microclots are a feature of coronaviruses of the category "SARS" (which is dubbed COVID [an abbreviation of "new COronaVIrus Disease", formely known as 2019nCoV] since December 2019).
1. Why does thrombosis occur in COVID? And what has the endothelial glycocalyx to do with microclots in COVID?
Thrombosis is a natural means of the body to restore tissues and the vasculature following injury. During infection with SARS-coronaviruses, the endothelium becomes damaged. The endothelium is the tissue with which organs and vessels are lined. An important part of the endothelium is the glycocalyx, a layer that protects the vasculature and organs against damage and septic shock. It does so by maintaining a barrier and creating healthy homeostasis (the in- and output of fluids, blood platelets and leukocytes).
The pathogenicity of COVID lies within the various and simultaneous acting of SARS on ACE2, platelets, the endothelium and in subsequent activation of inflammatory responses, the complement system and NET formation.
2. Why is a "perfectly functioning immune system" not sufficient against severe outcomes and endothelial damage in COVID?
Even as long ago as 20 years prior to the pending pandemic (2003), the first SARS-coronavirus was smart (evolved) enough to get through a properly functioning immune system. It knows exactly what it can expect from human immune systems.
The worst prospensity of both SARS-viruses is that they fool mitochondria in order to gain access to tissues and your RNA, without being detected by the immune system. Just to mention two remarkable traits of SARS-corona: it uses different caps on its proteins (ORFs) to go incognito and lowers its zinc compounds to turn of one major part of the alarm system of the immune sytem that would otherwise cut a virus to render it defenseless (= the Zinc Finger). Hence, not even being perfectly healthy does protect one against the severity of COVID: SARS does know how to turn off a properly functioning immune system. Would it meet with Interferon type I (IFN-I), the virus would be taken by an army of antiviral T-cells, but SARS-CoV-2 causes IFN deficiency. This is a major blow. One the virus gains access, damage to the endothelium is done.
3. Does this coronavirus act on the endothelium directly? Does that matter anyway?
To date, no evidence of direct actions on endothelial cells by SARS has been proved. However, even if endothelial cells do not have a "receptor to grant entry to SARS-CoV-2", the virus does act on ACE2. Platelets do also express TMPRSS2, the primer for ACE2-entry by this coronavirus.
In addition, activation of multiple cytokine storms (contrary to popular belief, there is not "one cytokine storm", but a simultaneous as well as a subsequent plurality of cytokine storms that leads up to deterioration) and hyperactivity of platelets, sepsis, loss of shear stress of the glycocalyx and IFN upregulation in epithelial cells all act on endothelial cells.
4. What other factors contribute to a severe outcome in COVID (ultimately, thrombo-embolism or microclots clogging the vasculature)?
It starts with one main receptor (not the sole receptor, M.B.) for SARS-infection, ACE2.
ACE2 is one of the major players in the Renin-Angiotensin-Aldosterone/Kallikrein Kinin System (RAAS/KKS), a fine-tuned system that regulates blood pressure, clot resolution, endothelial restoration and vessel integrity.
Decrease of ACE2 by SARS-infection upregulates Angiotensin II (AngII). AngII narrows blood vessels. Actions on AngII result in Oxidative Stress, activation of inflammasomes and enhanced clotting activities. Even at the early stages of SARS-infection, binding to ACE2, the breakdown of clots becomes impaired.
